Prostate-specific antigen (PSA) is a 33 kD glycoprotein synthesized in the epithelial cells of the prostate gland. It is a secreted serine protease of the kallikrein family. PSA has been shown to digest the seminal vesicle protein, semenogelin, parathyroid hormone-related protein, and insulin-like growth factor-binding protein-3 (Henttu P. et al. (1994) Ann. Med. 26: 157-164; Cramer S. D. et al. (1996) J. Urol. 156: 526-531). PSA is likely to act in semen production, but may have additional functions.
Genes encoding the three human kallikreins, tissue kallikrein (KLK1), glandular kallikrein (KLK2), and APS are located in a cluster at chromosome map position 19q13.2-q13.4 (Riegmen P.H. (1992) Genomics 14: 6-11). PSA shares more extensive homology with KLK2 than with KLK1. Both PSA and KLK2 are produced by prostate epithelial cells and their expression is regulated by androgens. Three amino acid residues were found to be critical for serine protease activity, residues H.sub.65, D.sub.120, and S.sub.213 in PSA (Bridon D. P. et al. (1995) Urology 45: 801-806). Substrate specificity, described as chymotrypsinogen-like (with KLK2) or trypsin-like (with PSA) is thought to be determined by S.sub.207 in PSA and D.sub.209 in KLK2 (Bridon et al., supra). KLK1 is chymotrypsinogen-like and expressed in the pancreas, urinary system, and sublingual gland. KLK1, like the other kallikreins, is made as a pre-pro-protein and is processed into an active form of 238 amino acids by cleavage of a 24 amino acid terminal signal sequence (Fukushima D. et al. (1985) Biochemistry 24: 8037-8043).
Adenocarcinoma of the prostate accounts for a significant number of malignancies in men over 50. There are over 122,000 new cases per year in the United States. Prostate-specific antigen (PSA) is the most sensitive marker available for monitoring cancer progression and response to therapy. Serum PSA is elevated in 25 to 92% of patients with prostatic carcinoma, depending upon tumor volume. Since PSA is also moderately elevated in patients with benign prostate hyperplasia, additional techniques are needed to distinguish between the two.
The discovery of polynucleotides encoding additional prostate specific molecules, and the molecules themselves, presents the opportunity to investigate disorders of the prostate, including benign hyperplasia and prostatic carcinoma. Discovery of molecules related to PSA satisfies a need in the art by providing new compositions useful in diagnosis, treatment, and prognosis of prostate cancer and hyperplasia.